1. Field of the Invention
The present invention relates generally to the fields of organic chemistry and antibacterial agents. More particularly, it concerns preparation of aminoglycoside derivatives, compositions comprising aminoglycoside derivatives, and methods of treating antibacterial infections with the same.
2. Description of the Related Art
The explosive growth of multidrug-resistant bacteria in hospitals and the community have led to an emerging crisis where an increasing number of antibiotics cease to be of microbiological and clinical usefulness (Boucher et al., 2009; Neu, 1992). As a result, there is a pressing need for novel classes of antibacterial agents with new or combined mechanisms of action that are active against multidrug-resistant bacteria and possess reduced likelihood for the development of resistance. Oligocationic antibacterials (OCAs) containing multiple positively charged amino functions or other cationic groups define a structurally diverse class of antibacterials with broad-spectrum activity and different modes of action (Peterson et al., 1985; Moore et al., 1986; Vaara and Vaara, 1983). This class of antibacterial agents can be further subdivided into non-amphiphilic OCAs such as aminoglycosides (Davis, 1987; Arya, 2007) but also amphiphilic OCAs comprised of the naturally occurring cationic antimicrobial peptides (Hancock and Sahl, 2006; Zasloff, 2002), synthetic mimics of antimicrobial peptides (SMAMPs) (Hamuro et al., 1999; Porter et al., 2000; Schmitt et al., 2007; Patch and Barron, 2004 Radzishevsky et al., 2007; Zorko et al., 2005; Liu et al., 2004; Tew et al., 2002; Chongsiriwatana et al., 2008 Som and Tew, 2008), synthetic oligocationic lipopeptides (Makovitzki et al., 2006; Andrä et al., 2005; Japelj et al., 2007; Majerle et al., 2003 Wakabayashi et al., 1999; Malina and Shai, 2005; Shai et al., 2006), oligocationic lipids (Vieira and Carmona-Ribeiro, 2006; David, 2001; Savage et al., 2002), and polymers (Palermo and Kuroda, 2009). The cationic charges of the OCA ensure accumulation at polyanionic microbial cell surfaces that contain acidic polymers, such as lipopolysaccharides, and wall-associated teichoic acids in Gram-negative and Gram-positive bacteria, respectively (Hancock and Sahl, 2006). Several OCAs including aminoglycoside antibiotics (gentamicin) and antimicrobial peptides (polymyxin B, defensins, gramicidin S variants, and others) transit the outer membrane by interacting at sites at which divalent cations crossbridge adjacent polyanionic polymers. This causes a destabilization of the outer membrane that is proposed to lead to self-promoted uptake of the OCAs and/or other extracellular molecules (Hancock and Sahl, 2006; Hancock and Bell, 1988). After transit through the outer membrane OCAs contact the anionic surface of the cytoplasmic membrane. Here depending on the structure of the OCA several scenarios can be envisaged. Amphiphilic OCAs can insert themselves into the cytoplasmic membrane thereby either disrupting the physical integrity of the bilayer, via membrane thinning, transient poration and/or disruption of the barrier function, or translocate across the membrane and act on internal targets (Hancock and Sahl, 2006). This mode of action has been shown to limit the risk of cross resistance (Hancock and Sahl, 2006; Zasloff, 2002; Chopra et al., 1997) and several amphiphilic OCAs including chlorhexidine and polymyxins are in use as antiseptics, disinfectants and antibiotics for several decades with little or no occurrence of resistance (Gilbert and Moore, 2005; Chen and Kaye, 2009). Non-amphiphilic OCAs such as aminoglycoside antibiotics must cross the bacterial membrane in order to bind to intracellular targets such as RNA, DNA and proteins. In this case co-administration with membrane permeabilizing agents such as ionic lipids can result in synergistic enhancements of the antibacterial action (Shelburne et al., 2004; Drew et al., 2009). It is generally believed that the selective bacterial cytotoxicity of OCAs is caused by the affinity of the net negative charge found on bacterial cell membranes in contrast to eukaryotic lipid bilayers which are typically made up of zwitterionic phospholipids (Hancock and Sahl, 2006).
Aminoglycoside antibiotics constitute a large family of clinically important non-amphiphilic OCAs used in the treatment of bacterial infections (Davis, 1987; Ayra, 2007). Aminoglycosides effect their antibacterial activity by interfering with ribosomal function (via binding to the A-site region on the 16S subunit of rRNA), which ultimately results in the disruption of protein biosynthesis (Moazed and Noller, 1987; Purohit and Stern, 1994). Although aminoglycoside antibiotics exhibit potent bactericidal activity, their widespread use has been compromised by the worldwide emergence and spread of aminoglycoside-resistant strains (Boucher et al., 2009) and toxicity (Giuliano et al., 1984; Tran Ba Huy et al., 1986). Several mechanisms cause resistance including decreased uptake into cells, as a result of activation of drug efflux pumps, modified membrane potential, changes in membrane composition, covalent modification of the drug and others (Magnet, S.; Blanchard, 2005; Taber et al., 1987; Wright et al., 1998; Shakya and Wright, 2007).
As a result, there is a pressing need for novel classes of antibacterial agents with reduced resistance.